CN1838958A - Methods of treating chronic obstructive pulmonary disease and pulmonary hypertension - Google Patents

Abstract

Methods of treating COPD and pulmonary hypertension using p38 Map kinase inhibitors in combination with one or more other active ingredients are disclosed.

Description

Methods of treating chronic obstructive pulmonary disease and pulmonary hypertension

application data

This application claims the benefit of US Provisional Application No. 60/497,376, filed August 22,2003.

technical field

The present invention relates to combinations of p38 kinase inhibitors and other active ingredients, pharmaceutical compositions thereof, processes for their preparation and their use in the treatment of chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (Pulmonary Hypertension).

Background technique

Tumor necrosis factor (TNF), interleukin-1 (IL-1) IL-8 and GM-CSF are important biological entities that are all pro-inflammatory cytokines. Together with a number of other related molecules, they mediate the inflammatory response associated with immune recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.

Levels of TNFα and IL-8 are elevated in the airways of patients with COPD, which may contribute to the pathogenesis of the disease (Patel IS et al. Inflammatory responses and clinical parameters of the airway epithelium in COPD. Eur Respir J. 2003 Jul;22(1):94-9). Circulating TNFα may also contribute to the weight loss associated with the disease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med., 161(4 Pt 1), 1179).

Aromatic heterocyclic compounds useful in the treatment of certain cytokine-mediated diseases are described in PCT publications WO 00/43384, WO 00/55139 and PCT application PCT/US02/28615. In US Publication No. 20030130309 a new use of the compounds described in WO 00/43384 for the treatment of diseases mediated by other cytokines including COPD is disclosed. US Publication No. 20030118575 describes the use of 1-[3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-[4-(2-morpholine-4- yl-ethoxy)naphthalen-1-yl]-urea as a new way to treat these diseases.

Corticosteroids, anticholinergics, theophylline, β2-agonists, and mucolytics are the most commonly prescribed respiratory drugs for COPD.

Naeije, R. et al pointed out that pulmonary hypertension is a common complication of COPD. Robert Naeije, R. et al, Crit Care. 2001; 5(6): 286-289, Nov. 3, 2001. It also states that pharmacological treatment of pulmonary hypertension can be performed in patients with advanced COPD and right-sided heart failure. Some recommended drugs are prostacyclin derivatives, endothelin antagonists, and inhaled nitric oxide. These drugs are considered to have a clinical effect in early pulmonary hypertension. Strange et al indicated that a therapy comprising endothelin receptor antagonists, nitric oxide (NO), PDE inhibitors, and gene therapy may be useful in the treatment of pulmonary arterial hypertension. Strange et al., Clinical Science (2002), 102, 253-268.

There are several main classes of drugs used to treat hypertension: diuretics, alpha-adrenergic blocking agents, beta-adrenergic blocking agents, angiotensin-converting enzyme (ACE) inhibitors, vasopeptidase inhibitors agents, vasopressin II receptor antagonists (AIIRAs), and calcium channel blockers. More recently, Kroetz et al. in US Patent Application No. 6,531,506 indicated that epoxide hydrolase inhibitors may also be useful in the treatment of hypertension. Examples of soluble epoxide hydrolase (sEH) inhibitors can be found in WO 03/002555, US Application Serial No. 10/172,457 by Ingraham, R. et al.

The literature described above supports the principle that inhibition of cytokine production using, for example, small molecule inhibitors of p38 MAP kinase in combination with one or more of the second active ingredients described above, would be useful in the treatment of chronic obstructive pulmonary disease. and/or pulmonary hypertension.

Summary of the invention

It is therefore an object of the present invention to provide a method for the treatment of chronic obstructive pulmonary disease (COPD) and/or pulmonary hypertension using a p38MAP kinase inhibitor and one or more second active ingredients.

Detailed description of the invention

In the treatment of diseases mediated by cytokines, specifically in the treatment of COPD and pulmonary hypertension, if one or more preferred active ingredients described here (hereinafter referred to as A), and one or more preferred A p38 kinase inhibitor (hereinafter referred to as B) is used together, and it is expected to obtain a beneficial therapeutic effect, especially an additive or superior effect, or an overall reduction of therapeutic side effects. The additional or superior effect of the pharmaceutical composition of the present invention is dose reduction, side effects reduction and/or time interval prolongation, compared to monotherapy using compounds A and B individually in a conventional manner. The above-mentioned effects can be observed both in the case when the two active ingredients are administered simultaneously in a single active substance formulation, and in the other when they are administered consecutively in different formulations. Additional benefits of adding B can be seen when A is injectable, specifically biologics. For example, cost reductions through interval and/or dose reductions.

Active ingredient A:

Within the scope of the present invention, active ingredient A is one or more of:

Including antihypertensive drugs known in the art, such as but not limited to: diuretics, alpha-adrenergic blocking agents, beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, Calcium channel blockers, vasopeptidase inhibitors, vasopressin II receptor antagonists (AIIRA) and epoxide hydrolase inhibitors, such as those described in U.S. Pat. No. 6,531,506 and WO 03/002555; particularly preferred for ibesartan and olmesartan;

Prostacyclin derivatives, endothelin antagonists and inhaled nitric oxide, PDE inhibitors and gene therapy;

Inhaled EGFR tyrosine kinase inhibitor (tyr kin inhibitor);

PI-3 kinase γ inhibitors, PDE4 inhibitors, FPRL-1/genome, TGFβr inhibitors, hCLCA1 blockers, MEK-1 inhibitors, JNK inhibitors, PAI-1 inhibitors, RARγ modulators and antioxidants;

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation, pain and fever. It contains paracetamol, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, phenoxyibuprofen calcium, flurbiprofen, indole domethacin, ketoprofen, carprofen, indoprofen, ketoprofen tromethamine, magnesium salicylate, methoxyphenamine sodium, mefenamic acid, oxaprozine, piroxicam, Sodium salicylate, sulindac, tolmetine, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lornoxicam, nicotine Mesulide, remifenzone, salicylate, tiaprofen acid, fluxamide, etc.;

Arofylline, NIK-616 and AWD 123-281.

Also within the scope of the present invention, active ingredient A is one or more

As an oral route:

Any pharmaceutically acceptable salt of roflumilast

Any pharmaceutically acceptable salt of cilomilast

As an inhalation route:

fluticasone propionate

salmeterol xinafoate

Budesonide

triamcinolone acetonide

Formoterol fumarate

ipratropium bromide and salbutamol.

Preferred embodiments of ipratropium bromide can be found in US Patent No. 6,739,333 and US Application No. 10/804,710.

Other preferred combinations for the treatment of COPD and/or pulmonary hypertension are p38 inhibitor compounds and any of the compounds disclosed in US Pat. No. 6,492,408, more preferably:

Inhibitors of cathepsins S, L, K and B are also within the scope of the present invention, for example in WO/0170232, WO/0119796, WO/0119808, WO/0170232, US Publication No. 20010016207, US Application No. 10/790,549, US Described in Patent Nos. 5,501,969, 5,736,357, 5,830,850, 5,861,298, 5,948,669, 6,030,946, 6,506,733, 6,353,017, 6,395,897, and 6,420,364.

Active ingredient B:

包含在本发明范围中的p38激酶抑制剂是选自美国专利6,319,921，6,358,945，5,716,972，US 5,686,455，US 5,656,644，US 5,593,992，US5,593,991，US 5,663,334，US 5,670,527，US 5,559,137，5,658,903，US5,739,143， US 5,756,499, US 6,277,989, US 6,340,685, US 5,716,955; and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/250 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/ 06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99 /58523, WO99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426 , WO99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO99 /32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO00/17175 , WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/ 71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01 /00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921 , WO 01/27089, DE 19842833, and compounds in JP 2000 86657, the disclosures of which are incorporated herein by reference. Within the scope of the present invention is the combination of the above B compound and component A in a single pharmaceutical composition, or the administration of the above B compound and component A alone.

Pharmaceutical compositions of the invention of particular interest are described in 6,319,921, 6,358,945, US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426 , WO 00/10563, WO 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, WO 00/55139 and WO 01/ p38 inhibitors disclosed in 36403.

In another preferred embodiment, the present invention relates to a drug combination comprising A and a p38 kinase inhibitor B, wherein the p38 kinase inhibitor B is selected from the compounds disclosed in WO 00/43384 and its corresponding U.S. Patent 6,319,921 .

In another preferred embodiment, the present invention relates to a drug combination comprising compounds A and B, wherein the p38 kinase inhibitor B is selected from the compounds disclosed in WO 00/55139 and the corresponding US Patent No. 6,358,945.

In another preferred embodiment, the present invention relates to a drug combination comprising compounds A and B, wherein the kinase inhibitor B is selected from the compounds disclosed in US Provisional Application No. 60/401,921.

The patent applications and patents mentioned above are hereby incorporated by reference in their entirety.

Particularly preferably, the present invention relates to a drug combination comprising A and B, wherein the p38 kinase inhibitor B is:

or a pharmaceutically acceptable salt thereof.

More preferably, the present invention relates to a drug combination comprising A and B, wherein the p38 kinase inhibitor B is:

and pharmaceutically acceptable salts thereof.

Of particular importance according to the present invention are combinations comprising A and B for pharmaceutical compositions as an active ingredient with anticytokine activity and one or more active ingredients with antihypertensive activity, and for these compositions For the treatment of respiratory diseases such as COPD and pulmonary hypertension.

The present invention also relates to a combination comprising A and B for preparing a pharmaceutical composition used in the treatment and/or prevention of COPD and pulmonary hypertension.

The invention also relates to pharmaceutical preparations comprising as active substance a combination of one or more compounds or pharmaceutically acceptable derivatives thereof, the combination comprising A and B, optionally with conventional excipients and/or carriers combination.

Anything related to the above-mentioned p38 kinase inhibitor B and compound A includes its "pharmaceutically acceptable derivative", and the "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester of the compound of the present invention, or when administered to a patient Any other compound capable of providing (directly or indirectly) the compound B, its pharmacologically active metabolite or pharmacologically active product of the present invention. It is to be understood that a pharmacologically active metabolite refers to any of those capable of being metabolized enzymatically or chemically to compound B of the present invention. This includes, for example, hydroxyl or oxidized derivatives of p38 compounds.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from their pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfuric acid, tartaric acid, Acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfuric acid and benzenesulfonic acid. Other acids such as oxalic acid, while not themselves pharmaceutically acceptable, can also be used as vehicles in the preparation of salts to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (eg sodium), alkaline earth metal (eg magnesium), ammonium and N-(C1-C4 alkyl)4+ salts.

In addition, the compounds of the invention comprise prodrugs of p38 compounds. Prodrugs include compounds that, when subjected to simple chemical transformations, convert to the product compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when the prodrug of the present invention is administered to a patient, the prodrug can be converted into the compound B of the present invention, thereby obtaining a desired pharmacological effect.

For therapeutic use, the combination of A and B according to the present invention may be administered in any conventional manner and in any conventional dosage. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, bolus injection, sublingual, transdermal, oral or inhalation.

Preferred modes of administration are inhalation, oral or intravenous.

The combined drugs of A and B according to the present invention can be administered separately, or administered in a joint preparation using an adjuvant or other active ingredients, wherein the adjuvant can improve the stability of the inhibitor, in some embodiments Facilitating administration of pharmaceutical compositions comprising them, providing increased dissolution or dispersion, increasing inhibitory activity, providing adjunct therapy, and the like. These combination treatments advantageously use lower doses of conventional treatments, thus avoiding possible toxicity and serious side effects that occur when the agents are used in monotherapy. Therefore, the combined drug of A and B can be physically combined with conventional treatment, or form a single pharmaceutical composition with other auxiliary agents. See Cappola et al. in this regard: US Patent Application No. 09/902,822, PCT/US 01/21860, and US Provisional Application No. 60/313,527, the entire contents of which are incorporated herein by reference. Suitable percentages (w/w) of compounds of the invention may vary and are within the scope of the invention to one of ordinary skill in the art.

As noted above, dosage forms of the compositions described herein comprise pharmaceutically acceptable carriers and adjuvants well known to those of ordinary skill in the art. These carriers and auxiliaries comprise, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum albumin, buffer substances, water, salts or electrolytes and cellulose substances. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstituted powders, granules, suppositories and transdermal patches. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements are established in the art and can be selected by one of ordinary skill in the art from available methods and techniques appropriate to a particular patient. In certain embodiments, for p38 Compound B, dosage levels vary between about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be used. For oral doses up to 2000 mg/day may be required. Reference can also be made to US Publication No. 20030118575 for literature on this aspect. Lower or higher dosages may be required, depending on particular factors, as will be understood by those of ordinary skill in the art. For example, the specific dosage and treatment regimen will depend on such factors as the patient's underlying health, the severity and course of the patient's disease or its management, and the judgment of the treating physician.

In another aspect, the present invention relates to a pharmaceutical composition suitable for inhalation comprising one or more salts A and one or more compounds B, optionally in the form of a salt, solvate or hydrate thereof. The active substances may either be combined in a single formulation, or contained in two separate formulations. Pharmaceutical compositions comprising active substances A and B in a single formulation are preferred according to the invention.

The present invention also relates to the use of A and B for the preparation of a combination comprising therapeutically effective amounts of A and B for the treatment of COPD and pulmonary artery disease by simultaneous or sequential administration, provided that treatment with a p38 kinase inhibitor is not contraindicated therapeutically. hypertension.

In the active substance combinations of A and B according to the invention, components A and B may be present in the form of their enantiomers, mixtures of enantiomers or racemic compounds.

According to the invention, the ratio of the two active substances A and B used in the active substance combination is variable. Active substances A and B may exist in the form of their solvates or hydrates. Depending on the choice of compounds A and B, the weight ratios used within the scope of the invention may vary on the basis of the different molecular weights of the various compounds and their different potencies. The determination of the weight ratio depends on the particular active ingredients A and B and is within the skill of the art.

The active substance combinations of A and B according to the invention can be administered by inhalation or nasal administration. For this, ingredients A and B must be made available in inhalable form. Inhalation formulations comprise inhalable powders, propellant-containing metered-dose aerosols, or propellant-free inhalation solutions or suspensions. The inhalable powders according to the invention comprising the active substances A and B may consist of the active substances themselves or their mixtures together with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalation solutions or suspensions also includes ready-to-use concentrates or sterile inhalable solutions. The formulations according to the invention may comprise the combination of active substances A and B in one formulation or in two separate formulations. These formulations within the scope of the invention are described in detail in the next part of the specification.

There are now four devices for administering the active substance combinations of A and B according to the invention to the lungs:

Pulmonary infusion set (Respimat) - (aqueous, ethanol (or any mixture thereof) solution or suspension)

Metered-dose inhaler, MDI (suspension or solution)

Dry Powder Inhaler, DPI (such as Spiriva)

A conventional nebuliser (UDV), usually with a unit-dose vial

The propellant-free inhalable solution or suspension according to the invention is administered in particular using an inhaler of the class capable of aerosolizing small quantities of liquid preparations within seconds For therapeutic doses to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are preferably capable of ejecting less than 100 µL of active substance solution in one ejection stroke with an average particle size of less than 20 µm to form an aerosol, in such a way that the inhalable portion of the aerosol corresponds to in a therapeutically effective amount.

Such containers for propellant-free delivery of metered liquid pharmaceutical compositions are described, for example, in International Patent Applications WO 91/14468 and WO 97/12687.

In another aspect, the invention relates to the above-mentioned pharmaceutical formulations in the form of propellant-free inhalable solutions or suspensions and devices suitable for administering these formulations, preferably using Respimat(R). Preferably, the invention relates to a propellant-free inhalable solution or suspension characterized in that the active substances A and B according to the invention are associated with a device named Respimat(R). Furthermore, the present invention relates to the aforementioned device for inhalation, preferably Respimat(R), characterized in that it comprises a propellant-free inhalable solution or suspension according to the invention as described above.

The invention preferably comprises an inhalable solution or suspension of the active substances A and B in one formulation. The term formulation also includes those containing components A and B in a two-chambered cartridge such as described in WO 00/23037. This disclosure is hereby incorporated by reference in its entirety.

The propellant-free inhalable solutions or suspensions according to the invention can take the form of ready-to-use concentrates or sterile inhalable solutions or suspensions, as well as the aforementioned solutions and suspensions designed for Respimat(R) . Ready-to-use preparations can be produced from concentrates, for example, by adding isotonic saline. Sterile ready-to-use formulations may be administered using energy-operated fixed or movable nebulizers that generate an inhalable aerosol by means of ultrasound or compressed air, based on the Venturi principle or other principles.

Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions or suspensions as described above, and devices suitable for administering these solutions, wherein the propellant-free inhalable solution Or the suspension can be in the form of a ready-to-use concentrate or a sterile preparation, characterized in that the device houses an energy-operated free-standing or movable nebulizer, which is based on the Venturi principle or other principles by means of ultrasound or compression Airborne form produces inhalable aerosols.

Respimat(R) solutions and UDV require that the drug substance be soluble and stable in either aqueous or ethanol vehicles. Solution MDI requires that the drug substance be soluble and stable in either the propellant, the mixture of propellants or the mixture of propellant and co-solvent (eg ethanol, water). Suspensions MDI, suspensions for Respimat(R) and DPI require that the active substance can be easily micronized into the inhalable range (less than 5 microns). Ideally, these micronized substances should have stable physicochemical properties such that there is no water absorption, aggregation and chemical decomposition. For suspension MDIs, the drug substance should be insoluble in the propellant (eg HFA 134a or HFA 227).

For combinations using the preferred p38 compounds, MDI devices with MDI suspension formulations using high pressure homogenization techniques known in the art are preferred. DPI devices are also preferred.

The following examples are intended to illustrate the present invention in more detail, but not to limit the scope of the present invention to the following embodiments according to the examples.

starting material

Component B, p38 inhibitor: BIRB 796 BS

1-[3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalene-1-yl ]-urea.

The above p38 component B used in the following Examples can be obtained as described in US Pat. No. 6,319,921 or 6,583,282.

preparation:

For preparation of oral dosage formulations for use in tablets, the formulations described in US Patent No. 6,565,880 or PCT/US 01/21860 can be used; for formulations for parenteral administration, see US Application No. 10/214,782.

Table 1

Core tablet formulations for 20, 25, 50, 100 and 200 mg core tablet formulations BIRB 796BS tablet 5mg 20mg 25mg 50mg 100mg 200mg Element Mg mg mg mg mg mg BIRB 796BS (milled) 5.000 20.000 25.000 50.000 100.000 200.000 lactose monohydrate 55.000 40.000 50.000 100.000 200.000 400.000 Povidone K30 3.1600 3.158 3.9475 7.8950 15.790 31.580 microcrystalline cellulose 30.000 30.000 37.500 75.000 150.000 300.000 pregelatinized starch 3.590 3.592 4.490 8.980 17.960 35.920 Sodium starch glycolate 2.000 2.000 2.500 5.000 10.000 20.000 Colloidal silica 0.500 0.500 0.625 1.250 2.500 5.000 Magnesium stearate 0.750 0.750 0.9375 1.875 3.750 7.500 Total piece weight 100.00 100.00 125.00 250.00 500.00 1000.00

Examples of combination drugs:

1) Element dose Component A: Cilomilast 15mg BID Component B (BIRB 796BS) 5-150mg BID

2) Element dose Component A: Roflumilast 250-1000mcg QD Component B (BIRB 796BS) 5-150mg BID

3) Element dose Component A: Salmeterol 25-50mcg BID Component B (BIRB 796BS) 5-150mg BID

4) Element dose Component A: Formoterol 12-24mcg bid Component B (BIRB 796BS) 5-150mg BID

5) Element dose Component A: Fluticasone 250-500mcg BID Component B (BIRB 796BS) 5-150mg BID

6) Element dose Component A: Budesonide 200-800mcg BID Component B (BIRB 796BS) 5-150mg BID

Other formulations containing specific active ingredients A and B can be obtained under experimental conditions, based on the teaching and examples provided herein, and from materials and methods known in the art. These variations are also within the scope of the present invention.

Any of the above combinations within the scope of the invention may be tested in animal models known in the art. Literature in this field can be found at:

Shapiro SD: animals models for COPD. Chest 2000; 117223S-227S.

Dawkins PA et al. Animal models of chronic obstructive pulmonary disease. Thorax 2001; 56: 972-977.

Mahadeva R, Shapiro SD. Chronic obstructive pulmonary disease. 3. Experimental animal models of pulmonary emphysema. Thorax 2002;57:908-914.

Wright JL, Churg A. Animal models of cigarette smoke-induced COPD. Chest 2002;122:301S-306S.

Takeyama, K. et al. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J. Physiol. Lung Cell Mol. Physiol 280: L165-L172, 2001.

Animal model: smoke-induced goblet cell tissue deformation in a subchronic rat smoke model

Subchronic exposure to smoke produces a significantly increased number of goblet cells in the airway epithelium and a marked increase in mucus production. Studies have shown that the signal transduction of p38MAP kinase may be involved in this pathway. The following studies can be used to evaluate the potency of the p38 MAP kinase inhibitors described herein together with one or more other active ingredients to inhibit smoke-induced changes in the lung.

Experimental steps:

exposure to smoke

Male Sprague-Dawley rats weighing 250-300 g were used in this study. Animals were housed in a temperature and humidity controlled room with free access to water and standard laboratory chow. Animals were randomly assigned as non-smoke-exposed control or smoke-exposed control and treatment groups, with 6 animals in each group. Rats in the smoke group will be exposed to 16 regular, unfiltered cigarettes (1.2 mg nicotine, 12 mg condensate) per day for 5 days.

On each day of exposure, 12 animals were housed individually in wire mesh cages in Plexiglas boxes (40 x 50 x 20 cm). Smoke was delivered into the box at a flow rate of 0.3 ml/s by lighting a cigarette in the chamber. The burn time of the cigarette is ~3 min. A ventilator in the box ensures that the cigarettes are dispersed quickly and evenly. Fresh air was delivered into the box at a flow rate of 2 l/min to remove fumes. At 20 minute intervals, smoke from new cigarettes was introduced into the chamber. All animals, including the control group, were not provided food or water during the smoke exposure period. At other times, animals had free access to food and water.

Treatment with a combination of active ingredient A and p38MAP kinase inhibitor B

To evaluate the effect of the combination of A and B according to the invention on goblet cell tissue deformation and mucus production, the animals were treated at least once a day with the vehicle or the combination of A and B as described above. Preferably, the dose of p38MAP kinase inhibitor is orally administered 10 or 30 mg/kg 1 hour before or after exposure to smoke every day. Treatment of animals with vehicle or combination started on day 1 of the smoke exposure period and continued for 5 days. Oral administration was performed by gavage in a volume of 3 ml/kg.

Tissue preparation and quantification of goblet cell production

Lungs were dissected and fixed in 4% buffered formalin and encapsulated in paraffin. The main bronchus on the left was used for immunohistochemical staining. Lung sections were sectioned to encompass the total length of the major intrapulmonary airways and serially stained with hematoxylin and eosin or alcian blue (AB)-periodic acid Schiff (PAS) to assess total epithelial cell areas and Areas for staining of intracellular mucus glycosides. Goblet cell production was determined by the bulk density of AB-PAS-stained mucus glycosomes at the epithelial mucosal surface using an imaging analysis system (Soft Imaging System, Münster, Germany). AB-PAS-positive staining area, number of goblet cells and total epithelial cell area were detected on the basement membrane with a length of 2 mm.

statistics

All data are presented as mean ± SEM. Statistically significant differences between groups were determined using a one-way analysis of variance (ANOVA). When significant differences were identified in ANOVA, Scheffé's F test was used to correct for multiple comparisons. P<0.05 for the null hypothesis was taken as an indication of statistically significant differences.

Inhibition of smoke-induced goblet cell tissue deformation

In vehicle control animals, the airway epithelium should contain very few goblet cells. Smoke inhalation (16 cigarettes/day for 5 days) usually resulted in at least a 3-fold increase in goblet cell numbers. Treatment with the preferred combination of A and B will dose-dependently inhibit this increase.

All literature, patents and publications cited in this application are hereby incorporated by reference in their entirety.

Claims (8)

1. A method for treating COPD or pulmonary hypertension, comprising administering to a patient a therapeutically effective amount of one or more active ingredients A and a therapeutically effective amount of one or more p38 kinase inhibitors; Wherein the active ingredient A is selected from: Diuretics, alpha-adrenergic blocking agents, beta-adrenergic blocking agents, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, vasopeptidase inhibitors, vasopressin II receptors Antagonists (AIIRA), epoxide hydrolase inhibitors; Prostacyclin derivatives, endothelin antagonists, inhaled nitric oxide, PDE inhibitors; Inhaled EGFR tyrosine kinase inhibitors; PI-3 Kinase γ Inhibitors, PDE4 Inhibitors, FPRL-1/Genome, TGF βr Inhibitors, hCLCA1 Blockers, MEK-1 Inhibitors, JNK Inhibitors, PAI-1 Inhibitors, RARγ Modulators, Antioxidants ; Non-steroidal anti-inflammatory drugs (NSAIDs); Arrophylline, NIK-616, AWD 123-281; Roflumilast, cilomilast, fluticasone propionate, salmeterol xinafoate, budesonide, triamcinolone acetonide, formoterol fumarate;

and inhibitors of cathepsins S, L, K and B. 2. The method according to claim 1, wherein the p38 kinase inhibitor is a compound or a pharmaceutically acceptable salt thereof selected from: 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl)phenyl)naphthalen-1-yl ] urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)phenyl)naphthalene- 1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl ) naphthalene-1-yl] urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminophenyl)naphthalene-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)phenyl)naphthalen-1-yl ] urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)phenyl)naphthalene- 1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2-yl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-furan-2-yl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl -pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene-1 -yl]urea; 1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-piperidin-1-ylmethyl-phenyl)naphthalen-1-yl] urea; 1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-(4-methylpiperazin-1-yl)methylphenyl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-bis(morpholin-4-yl-methyl)phenyl ) naphthalene-1-yl] urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-pyridin-4-ylmethyl- Pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorph Lin-4-ylmethyl)pyridin-3-yl)naphthalene-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-ylmethyl) Pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-tetrahydropyran-4-yl Methyl-pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydro Thiophen-3-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(imidazol-1-ylmethyl )pyridin-3-yl)naphthalen-1-yl]urea; 1-[2-(3-Dimethylaminomethylphenyl)-5-(1-methyl-cyclohexyl)-2H-pyrazol-3-yl]-3-[4-(6-morpholine -4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea; 1-[2-(5-(1-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6 -morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-methoxy-5-(2 -morpholin-4-yl-ethoxy)phenyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholine-4- yl-ethoxy)phenyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(dimethylamino)phenyl) Naphthalene-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3-(methylsulfonyl)phenyl) Naphthalene-1-yl]urea; Methyl 5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene-1-yl]ureido}thiophene-2-carboxylate; 5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene-1-yl]ureido}thiophene-2-carboxylic acid methylamide ; 5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene-1-yl]ureido}-1H-pyrrole - Methyl 2-carboxylate; 5-tert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene-1-yl]ureido}-1H-pyrrole -2-Carboxymethylamide; 2-Acetamido N-(5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalene-1-yl]ureido}thiophene- 2-ylmethyl)acetamide; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohept-1-enyl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl-ethylamino)cyclohexyl -1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohept-1-enyl)naphthalene -1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-4-yl-methyl Amino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(dimethylaminoethylamino )cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-3-yl-methyl Amino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phenyl-methylamino) Cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-phenylethylamino )cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-yl-methyl Amino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyridin-2-yl) -Ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-piperidin-1- Base-ethylamino)cyclohex-1-enyl)naphthalene-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-imidazol-4-yl -Ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-2-yl-methyl Amino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(4-methoxy phenyl)ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-ylmethyl-3-oxo-cyclohexyl -1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-tetrahydrothiophen-3-ylmethyl) -3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-thiomorpholin-4-ylmethyl) -3-oxo-cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperazin-1-ylmethyl)-3-oxo -cyclohex-1-enyl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-{6-oxo-1-(tetrahydro -pyran-4-ylmethyl)-1,2,3,6-tetrahydro-pyridin-4-yl}naphthalen-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-oxo-1-pyridine-4 -ylmethyl-piperidin-4-yl)naphthalen-1-yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl-1,2,3 , 6-tetrahydro-pyridin-4-yl)naphthalene-1-yl]urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridine-4 -yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl]urea; 5-tert-butyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1-yl ]ureido}thiophene-2-carboxylate methyl ester; 5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl) Naphthalene-1-yl]ureido}pyrrole-2-carboxylic acid methyl ester; 5-tert-butyl-1-methyl-3-{3-[4-(6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl) Naphthalene-1-yl]ureido}pyrrole-2-carboxylic acid methylamide; Methyl 5-tert-butyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalene-1-yl]ureido}thiophene-2-carboxylate; 5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalene-1-yl]ureido}pyrrole-2- methyl carboxylate; 5-tert-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalene-1-yl]ureido}pyrrole-2- Carboxylic acid methylamide; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methylphenyl)-naphthalene-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[3-(4-morpholin-4-yl-methylphenyl)-naphthalene-1 -yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-yl-methylfuran-2-yl)- Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl) -naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-morpholin-4-yl)ethylphenyl)- Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminomethylphenyl)-naphthalene-1-yl] - urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl )-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl )-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- Methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)- Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(morpholine-4 -yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-(morpholin-4-yl-methyl)phenyl) -naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperazin-1-yl-methyl)phenyl)- Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(piperidin-1-yl-methyl)phenyl)-naphthalene-1- base]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridine-2- Base) ethylamino) cyclohexenyl)-naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(pyridin-4-yl)ethylaminomethyl) Phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methylaminomethyl)phenyl) Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3,4-dimethoxy phenylmethyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1,6-dihydro-pyridin-3-yl) Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- Methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- Methyl)imidazol-1-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl)imidazol-1-yl ) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-3-yl-methyl Base)-3-hydroxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutylamino) Pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methyl Base)-3-hydroxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(4-methyl-3-carbamoylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholine-4- Base-methyl)pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(imidazol-2-yl-methyl Base)-3-hydroxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hydroxymorpholine-4 -yl-methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-2-methoxy Ethyl-N-methylaminomethyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholine-4 -yl-methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl- Methyl)cyclohexenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-yl-methyl Base)-3-hydroxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-two-( 2-methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3-cyanopropoxy )pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methyl Base-piperidinyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-two-( 2-cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-yl)-naphthalene -1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl Base)-3-hydroxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-yl -methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-formylaminomorpholine -4-yl-methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3- Oxo-piperazin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl Base) pyridin-3-yl) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4-hydroxybutoxy) Pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[3-tert-butyl-1'H-[1,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridine-3 -yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl Base)-3-methoxyphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholine-4 carbonyl)pyridine Azin-2-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran-4- Base-amino)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridine -3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6-dimethyl Morpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- Methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-aminopyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl )pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-oxo-1,6-dihydropyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-( Lin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- 4-carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5- Aza-bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbamoylphenyl)naphthalene-1-yl]- urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyano Ethyl)-N-(pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyano Ethyl)-N-(pyridin-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyano Ethyl)-N-(tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- Methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-morpholine-4- Base-propyl)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxy propyl)amino)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxy propyl)-N-methylamino)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazole-5-yl]-3-[4-(6-(morpholin-4-yl- Methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl) -naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-N-di-(2- Cyanoethyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(4-carbamoylphenyl)naphthalene-1-yl]- urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydro Thiopyran-4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl -amino)pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[3-tert-butyl-1'-(3-cyanopropyl)-1'H-[1,4']bipyrazole-5-yl]-3-[4-(6-( Lin-4-yl-methyl)pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methylsulfinylphenyl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methylsulfonylphenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-sulfonamidophenyl)naphthalene-1-yl]- urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)carbonylphenyl)naphthalene-1- base]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran-4-yl -amino)pyrazin-2-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(methylcarbonylamino)pyridine- 3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)phenyl)- Naphthalene-1-yl]-urea; 1-[3-tert-butyl-1'-(3-methylthiopropyl)-1'H-[1,4']bipyrazole-5-yl]-3-[4-(6-( Morpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-carbonyl)pyridin-3-yl) -naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl- Methyl)pyrazin-2-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-aminopyridin-3-yl)naphthalene -1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-methylpiperidine- 4-yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo Substituted-piperazin-1-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-carbonyl )pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N,N-two-(2 -methoxyethyl)aminomethyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholine -4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4-yl -amino)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl Base) pyrazin-2-yl) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl -Methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperazine-1- Base-methyl)pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-oxy)pyridin-3-yl) Naphthalene-1-yl]-urea 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-amino)pyridin-3-yl)naphthalene -1-yl]-urea; 1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- Methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-carbamoylpyridin-3-yl)naphthalene-1-yl]- urea; 1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl )pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl-methyl Base) phenyl) naphthalen-1-yl] - urea; 1-[3-tert-butyl-1'-methyl-1'H-[1,4']bipyrazole-5-yl]-3-[4-(6-(morpholin-4-yl- Methyl)phenyl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- Methyl)pyridin-3-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(pyridin-3-yl-amino)pyrimidin-5-yl)naphthalene -1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl-amino )pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridine-3- Base) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5-b]pyridine -6-yl)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl Base) pyridin-3-yl) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5-yl) Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5-yl ) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamoylphenyl)naphthalene-1-yl] - urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl-methyl )pyridin-3-yl)naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3-yl) Naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(hydroxy-pyridin-3-yl-methyl)pyridine-3- Base) naphthalene-1-yl]-urea; 1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl Base) pyrimidin-5-yl) naphthalene-1-yl]-urea; 1-(3-cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(3-fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(3,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(3-iodo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-m-tolyl-urea; 1-(4-methylthio-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2,5-dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-2-yl-urea; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-3-phenyl-urea; 1-(3-Chloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,6-trichloro-phenyl)-urea; 1-(2-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(4-methyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2,3-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(2-Chloro-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2,4-dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(4-methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2,3-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(4-cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3,4,5-trimethoxy-phenyl)-urea; 1-biphenyl-4-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2,5-difluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(4-Benzyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2-Methylthio-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(4-fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,5-trimethyl-phenyl)-urea; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethyl-phenyl)-urea; 1-(3-methylthio-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-fluoro-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea 1-(5-Chloro-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Isopropyl-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-Isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(3-Ethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 4-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-benzoic acid ethyl ester 1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea 1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethylthio-phenyl)-urea 5-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-isophthalic acid dimethyl ester 1-(3-cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea 3-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-benzoic acid ethyl ester 1-(5-tert-butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Methylthio-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-pentyloxy-biphenyl-3-yl)-urea 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-benzoic acid methyl ester 1-(2,5-diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-Benzothiazol-6-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea N-(2,5-diethoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}- Phenyl)-benzamide 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-phenoxy-phenyl)-urea 1-(5-Ethylsulfonyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- Urea 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-N-phenyl-benzene Formamide 1-(2-Methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-3-[4-(6-morpholin-4-ylmethyl -pyridin-3-yl)-naphthalen-1-yl]-urea 1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-benzene Sulfonamide 1-[3-(2-Methyl-[1,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridine-3 -yl)-naphthalen-1-yl]-urea 1-(3-methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea 1-(2,4-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-Chloro-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethylthio-phenyl)-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-phenoxy-phenyl)-urea 1-(2-Methoxy-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea 1-(3,5-di-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(2-tert-butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea 1-(3-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(4-tert-butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(5-chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea 1-(5-isopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(5-sec-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- Urea 1-(5-tert-butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene- 1-yl]-urea 1-(5-tert-butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- Urea 1-(5-tert-butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl} -naphthalen-1-yl)-urea 1-(5-tert-butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)-naphthalene-1-yl]-urea 1-(5-tert-butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea 1-(5-tert-butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]-naphthalene-1-yl }-urea 1-(5-tert-butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea 1-(5-tert-butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1- base]-urea 1-(6-tert-butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene -1-yl]-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl-phenyl)-urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy-phenyl)-urea 1-[5-(1,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl )-naphthalen-1-yl]-urea 1-[5-tert-butyl-2-(1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- Naphthalene-1-yl]-urea 1-[5-tert-butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl )-naphthalen-1-yl]-urea 1-[5-tert-butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene- 1-yl]-urea 1-[5-tert-butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl -pyridin-3-yl)-naphthalen-1-yl]-urea 1-[5-tert-butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene- 1-yl]-urea N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-acetamide 1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-acetamide; 1-[5-tert-butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridine- 3-yl)-naphthalen-1-yl]-urea; 1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea; 1-{5-tert-butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4- (6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea; 1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl]-urea; 1-[5-tert-butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl- Pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl )-naphthalen-1-yl]-urea; 1-[5-tert-butyl-3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[ 4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl- Pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea; 1-[5-(1-cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- Naphthalene-1-yl]-urea; 1-[5-tert-butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl- Pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-[1,3]dioxolan-2-yl-pyridin-3-yl)-naphthalene- 1-yl]-urea; 1-(5-tert-butyl-2-pyrrolidin-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1- base]-urea; 1-(5-tert-butyl-2--dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea; 1-(5-tert-butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridine-3- Base]-naphthalen-1-yl}-urea; 1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea ; 1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1 -yl]-urea; 1-(5-tert-butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene- 1-yl]-urea; 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalene-1-yl]-urea; N-acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1 -yl]-ureido}-phenyl)-acetamide; 1-(6-tert-butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6 -morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- urea; 1-(5-tert-butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea; 1-(5-tert-butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea; 1-(5-tert-butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene -1-yl]-urea; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-bis(methylsulfonyl)amine; 1-[5-tert-butyl-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridine- 3-yl)-naphthalen-1-yl]-urea; 1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl ]-urea; 1-[4-(6-{[di-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalene-1-yl]-3-(5-tert Butyl-2-methoxy-phenyl)-urea; N-[1-(5-{4-[3-(5-tert-butyl-2-methoxy-phenyl)-ureido]-naphthalene-1-yl}-pyridin-2-ylmethyl) -pyrrolidin-3-yl]-acetamide; 1-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- Pyridin-3-yl)-naphthalen-1-yl]-urea; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-propionamide; 1-(5-tert-butyl-2-methyl-benzoxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene- 1-yl]-urea; 1-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethanesulfonyl-phenyl)-urea; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-isobutyramide; 2-(4-tert-butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-ureido}-phenoxy )-acetamide; 1-(5-tert-butyl-2-oxo-2,3-dihydro-benzoxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridine- 3-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene- 1-yl]-urea; 1-(5-tert-butyl-benzoxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- urea; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-benzenesulfonamide; Ethylsulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- Urea group}-phenyl)-amide; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)-naphthalene-1-yl]- urea; 1-(5-tert-butyl-2-methylthio-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]- urea; 1-(5-tert-butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1- base]-urea; 2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl )-naphthalen-1-yl]-ureido}-phenyl)-amide; N-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)-ureido]-naphthalene-1-yl}-pyrazin-2-yl)-methanesulfonamide; 1-[4-(6-{[di-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalene-1-yl]-3-(5-tert-butyl -2-methoxy-phenyl)-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]- Naphthalene-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl] - urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridine-3- Base]-naphthalen-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)-pyridin-3-yl ]-naphthalen-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-naphthalene-1 -yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2-ylmethyl )-amino]-methyl}-pyridin-3-yl)-naphthalene-1-yl]-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)-pyridine-3- Base]-naphthalen-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)-pyridine- 3-yl]-naphthalen-1-yl}-urea; 1-(5-{4-[3-(5-tert-butyl-2-methoxy-phenyl)-ureido]-naphthalene-1-yl}-pyridin-2-ylmethyl)-piperidine -3-Carboxamide; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-114-thiomorpholin-4-ylmethyl)-pyridine-3- Base]-naphthalen-1-yl}-urea; 1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- Pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]- Naphthalene-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]-pyridin-3-yl} -naphthalen-1-yl)-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]- Methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl Methyl)-pyridin-3-yl]-naphthalene-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridine-3- Base]-naphthalen-1-yl}-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1-ylmethyl] -pyridin-3-yl}-naphthalen-1-yl)-urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-naphthalene-1-yl}- urea; 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-naphthalen-1-yl] - urea; 1-(6-tert-butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholine-4 -ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1 -yl]-urea; N-(5-{4-[3-(5-tert-butyl-2-methoxy-phenyl)-ureido]-naphthalene-1-yl}-pyridin-2-yl)-acetamide; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-N-methyl-acetamide; N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-2,2,2-trifluoro-acetamide; 1-(5-tert-butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalene-1-yl} - urea; [4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-carbamic acid 3-tert-butyl-phenyl ester; and N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-urea Base}-phenyl)-methanesulfonamide. 3. The method according to claim 1, wherein the p38 kinase inhibitor is a compound selected from the group consisting of:

and 4. The method according to any one of claims 1-3, wherein active ingredient A is ibesartan or olmesartan. 5. The method according to any one of claims 1-3, wherein the active ingredient A is paracetamol, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, difluoro Nisal, etodolac, phenoxyibuprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketoprofen tromethamine, magnesium salicylate, Mefenamic acid sodium, mefenamic acid, oxaprozine, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, alto Coxib, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, remifenzone, salsalate, tiaprofen acid, or fluthamide. 6. The method according to any one of claims 1-3, wherein the active ingredient A is fluticasone propionate, salmeterol xinafoate, budesonide, triamcinolone acetonide or formoterol fumarate. 7. A method for treating COPD or pulmonary hypertension, comprising administering to a patient a therapeutically effective amount of one or more active ingredients A and a therapeutically effective amount of one or more p38 kinase inhibitors; Wherein the active ingredient A is selected from ipratropium bromide and albuterol. 8. The method according to claim 7, wherein the p38 kinase inhibitor is a compound selected from the group consisting of:

and